Lamotrigine plus Valproate: Better than Lamotrigine Alone for Bipolar Depression
In a study comparing valproate monotherapy with the combination of lamotrigine and divalproex (Valproate) extended release (ER), the combination appeared more effective in bipolar depression. At the American College of Neuropsychopharmacology meeting in December 2009, Vivek Singh, Charles Bowen, Richard Weisler, and colleagues from The University of California, San Diego reported on the randomized, double-blind, eight-month maintenance study of bipolar depressed patients.
Patients who could be stabilized for two consecutive weeks on the combination treatment of both lamotrigine and divalproex were then randomized to either lamotrigine alone or the combination for the duration of the study. Most of the data collected about these 87 subjects favored the treatment with the combination (lamotrigine plus divalproex) compared with lamotrigine alone. Combination therapy was superior for manic symptomatology and resulted in lower rates of unanticipated worsening of depression (greater than 20 points on the Montgomery-Asberg depression rating scale (MADRS)) that led to termination from the study than lamotrigine monotherapy did.
EDITOR’S NOTE: These data are interesting for several reasons. One is the generally good tolerability of the combination. While divalproex added to lamotrigine will essentially double lamotrigine blood levels and can increase risk of a serious rash, the two drugs are widely used in combination in the treatment of patients with seizure disorders with both good efficacy and tolerability. This may be attributable in part to the fact that divalproex has the ability to increase brain GABA, while lamotrigine inhibits glutamate release, and the combination may thus be associated with dual mechanisms of increasing GABA inhibition and decreasing glutamatergic over-excitation which together would prevent too rapid cell firing and behavioral dysregulation.
This study also has interesting parallels with the results of the large BALANCE study conducted recently in Europe, in which the combination of lithium and divalproex (Valproate) was found to be substantially more effective than divalproex alone and, to a lesser extent, more effective than lithium alone as well. These two studies add to the literature suggesting that treatment with combinations of mood stabilizers may be superior to monotherapy.
This conclusion is also supported by several studies from Case Western Reserve University in Cleveland of both adults and children with bipolar disorder who were initially stabilized on the combination of lithium and divalproex and then randomized to monotherapy with either agent. In both patient populations there was a very high relapse rate upon the switch to monotherapy and, at least in the children with bipolar disorder, a very high re-response rate once the combination of lithium and divalproex was reinstituted.
Clinicians have long used combination therapy and, at times, complex combination therapy in order to establish more substantial long-term responses or remission, but until recently there was not an extensive controlled clinical trials literature to support this procedure. Now there is support for combination therapy in overall superior treatment outcome and the prevention of both manias and depressions with the combination of lithium and divalproex, and now in bipolar depression with the combination of divalproex and lamotrigine compared with lamotrigine alone.
Some clinicians and investigators, such as Paul Grof and colleagues, have extolled the virtues of monotherapy compared with combination therapy and, while there is a small subgroup of patients who do well on long-term lithium monotherapy, this appears, at least in the U.S., to be a very small minority of patients, and much more often combinations are required to achieve short- and long-term stability. Even in the current study of Singh and colleagues, only 87 of the 165 subjects originally enrolled were able to be randomized, meaning that in a period of open treatment for up to eight weeks, only about half the patients treated with the divalproex/lamotrigine combination for a current depression or a depression within the past six months were able to sustain low depression scores for a period of two weeks.
Indirectly, this indicates that other combinations of treatments or additional augmenting agents would be required for this other half of the patients who failed to show initial mood stabilization. These data are very much like those of Calabrese and colleagues who found that only about one-quarter of the patients evaluated on the combination of lithium and divalproex who had rapid cycling bipolar disorder were able to be stabilized for a short period of time on this combination. It appears that not only are monotherapies with mood stabilizers often much less satisfactory than combination therapy, but one-half to two-thirds of patients do not even respond satisfactorily enough to the combination in the first place, and would then need other and potentially more complicated treatment strategies from the outset.
The data with atypical antipsychotic augmentation would appear to conform with this same theory. Quetiapine (Seroquel) is FDA-approved as an adjunct to lithium or divalproex. Its addition has resulted in superior prevention of both manic and depressive episodes compared with continuation of lithium or valproate alone (and with the addition of a placebo). While there is now evidence (from the SPARKLE study described in the BNN (2009) Vol. 13, Issue 3) that quetiapine monotherapy is also more effective than placebo, it remains to be seen whether a mood stabilizer (lithium or divalproex) plus an atypical such as quetiapine would be more highly effective in selective patient populations compared with quetiapine alone. Quetiapine monotherapy in the SPARKLE study showed about equal efficacy to lithium monotherapy.
There is also a strong clinical-trials literature indicating the superiority of the combination of an atypical plus a mood stabilizer in the treatment of acute mania. These data extend to almost all of the atypical antipsychotics studied in a controlled fashion. Since we and most other clinicians and investigators have endorsed the general principle that the treatments that are successful in achieving acute mood stabilization/remission are the ones most likely to sustain this response in long-term prophylaxis, there is further rationale for continuation of a mood stabilizer and an atypical during the maintenance phase, particularly if there is good tolerability and no problematic emergence of side effects. Thus, long-term tolerability, which varies considerably among the different atypicals, becomes an important variable in the choice of agents to be considered in acute treatment as well as long-term prophylaxis.